We are requesting funds for the competitive renewal of our Program Project Grant (PPG) from NIDA, entitled Molecular Neurobiology of Drug Addiction. The PPG supports a series of highly interactive and multidisciplinary studies aimed at delineating the molecular and cellular mechanisms underlying opiate and cocaine addiction. Each research area represents an integration of molecular, biochemical, electrophysiological, neuropharmacological, neuroanatomical, and behavioral levels of analysis, which are focused very tightly around the roles played by two transcription factors, CREB and ?FosB, and a small number of their putative target genes, in the brain's reward pathways in opiate and cocaine action. The PPG is organized into a small Administrative Core, two scientific Cores, and four Projects. The Transgenic Core (PI, Eric Nestler) is responsible for breeding the many lines of transgenic and knockout mice, and for constructs for viral-mediated gene transfer, to be utilized in the proposed research. The Core is also responsible for the construction of several new lines of mutant mice, including those with inducible tissue-specific transgenes and knockouts. The Behavioral Core (PI, David Self) is responsible for providing to individual Projects a broad battery of behavioral tests in mice and rats relevant to drug abuse and addiction. The capacity of the Core is expanded through a subcontract with Jane Taylor at Yale. Project 1 (PI, Eric Nestler) is a continuation of a productive and collaborative effort among several laboratories to study the role of CREB in the mesolimbic dopamine reward circuit, comprised of dopamine neurons in the ventral tegmental area (VTA) and their projection regions, in particular, the nucleus accumbens (NAc). A substantial body of evidence supports our hypothesis that opiate and cocaine induction of CREB activity in these regions is an important mediator of long-term drug effects in both of these brain reward regions. Project 2 (PI, Rob Malenka via a Stanford subcontract) focuses on characterizing the functional consequences of specific drug-induced molecular adaptations in the mesolimbic dopamine system in neurophysiology and synaptic plasticity models. The Project concentrates on the cellular actions of CREB and ?FosB and a small number of putative target genes in the NAc. Project 3 (PI, Eric Nester) is a new effort, which consolidates the PPG's investigations of mechanisms of gene regulation in the VTA-NAc in response to chronic opiate or cocaine administration, with a particular focus on the role played by CREB and ?FosB. A major aspect of the Project's research is drug regulation of chromatin remodeling mechanisms, which have provided novel insight into the long-lasting effects of the drugs on gene regulation. Project 4 (PI, David Self) is a continuation of efforts to study the role of drug-induced molecular adaptations in the mesolimbic dopamine system in animal models of drug reinforcement and craving. Project investigators focus on the behavioral phenotype induced by CREB and ?FosB, and a small number of putative target genes, within this reward circuit. Together, the proposed program of research is tightly focused on transcriptional mechanisms in drug action, and will continue to contribute to a better understanding of drug addiction at the molecular, cellular, and systems levels. PROGRAM PROJECT CHARACTERISTICS